STOPPING THERAPY: MIXED RESULTS ADDING UP TO STRATEGY?

Despite the encouraging talk about "HIV eradication" several years ago, results have been disappointing. Most people who discontinued anti-HIV therapy after long-term viral suppression experienced rapid rebound in virus levels, and the latest estimates of time to a "cure" are up to sixty years and still rising.

However, a number of intriguing results in people who have had to stop and restart therapy several times have begun to suggest ways to help the body's immune system take over some of the work. Following the spectacular results of "The Berlin Patient," whose body seems to have controlled HIV after therapeutic discontinuation for two years now, researchers have started to look at "planned therapeutic interruptions."

A number of immunologists have observed that the HIV-specific immune response seems to wane after several years of virtually complete viral suppression by anti-HIV treatment. However, several patients have had several therapeutic interruptions due to treatment toxicity, the time to viral rebound seems to have gotten longer with each treatment cessation. Researchers are now investigating the long-term impact of "planned therapeutic interruptions" as a way of "training" the immune system to control HIV. Because simultaneous discontinuation of all treatments theoretically removes evolutionary pressure on HIV to develop resistance, re-starting therapy after such a treatment interruption should result in complete suppression of the virus again. However, leading investigators are warning patients and physicians, "Don't try this at home." Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Disease, said, "The strategy needs to be tested. The stop-and-go game can lead to drug resistance even if it looks so far like the wild-type strain remains."

HALTING PCP PROPHYLAXIS FOLLOWING IMMUNOLOGIC REBOUND

In a study recently published in the New England Journal of Medicine, investigators from the Swiss HIV Cohort Study looked at the effects of halting PCP prophylaxis in patients whose immune systems had been substantially damaged by HIV. These patients later experienced CD4+ count increases to greater than 200 cells and fourteen percent of total lymphocytes. Patients were examined every three months after study entry and were followed for almost a year.

During follow-up, none of the 262 study participants developed PCP, although nine patients had prophylaxis resumed, and two patients died.

The study also examined the impact of stopping PCP prophylaxis on rates of Toxoplasma gondii. Trimethoprim/Sulfamethoxazole, the most common drug used for PCP prophylaxis, may also prevent toxoplasmosis. No cases of toxoplasmic encephtalitis were seen during the follow-up period.

Similar results have also been reported from smaller studies in Tampa, FL, and from Utrectht in the Netherlands. N

BILL GATES DONATES $25 MILLION FOR AIDS VACCINE SEARCH

The International AIDS Vaccine Initiative (IAVI) recently announced that it has received a $25 million grant from Microsoft mogul Bill Gates and his wife Melinda through the Wiliam H. Gates Foundation in Seattle. According to representatives of IAVI, the funds will be distributed over a five-year period and will be used to develop three new vaccine candidates.

In making the grant, Gates said, "Vaccines are one of the most far-reaching and effective technologies of our time. A widely distributed vaccine can help make the goal of a world without AIDS a reality. Shortening the time it will take to find a vaccine can save millions of lives. We're proud to be supporting the heroic work of IAVI in this gift."

Leaders in the world-wide fight against AIDS have applauded the Gates's gift. James D. Wolfensohn, President of the World Bank, said, "I am delighted that the Gates Foundation has stepped in so generously to support IAVI's work to speed up development of an AIDS vaccine. We see an AIDS vaccine difficult as it will be to develop, test and deploy as one vital component to a much stronger global effort that is urgently needed to combat the pandemic."

IAVI has begun an innovative series of partnerships that bring together corporate sponsors, leading researchers and government programs to develop various AIDS vaccine candidates. N

MORE WORK NEEDED ON SALVAGE THERAPY

A large group of advocates for people with HIV/AIDS, calling themselves the Coalition for Salvage Therapy, is demanding that pharmaceutical companies speed up efforts to test new treatments for use in heavily pre-treated patients. According to Coalition members, many pharmaceutical companies developing products that should be useful for such patients are studying mostly therapy-naive patients in order to get marketing approval.

AIDS Action Baltimore's Lynda Dee, who serves as the Chair of the Coalition, said, "Most research on treatments for life-threatening diseases is driven by the survival of the patients. Unfortunately, in AIDS, this trend is reversed; companies, for whatever reason, are driven by research that will make their drugs appear in the best light-usually patients with no prior anti-HIV therapy. What we're trying to do is to put the focus back on the patients most in need of good research and effective therapies. That's where the public health priority lies."

In recent results from ACTG 359, presented at the Second International Workshop on Salvage Therapy for HIV Infection, patients who had received extensive indinavir therapy were randomly assigned to receive various combinations of ritonavir, saquinavir, nelfinavir, adefovir and delavirdine. In this study, only about thirty percent of patients had achieved undetectable plasma HIV RNA levels after sixteen weeks of treatment. Ritonavir and nelfinavir were approximately equivalent in their ability to suppress RNA levels. Delavirdine was superior to adefovir, and the combination of the two drugs was no better than delavirdine alone.

In a similar finding from ACTG 372, which tested combinations of abacavir, efavirenz, adefovir, nelfinavir, and older nucleoside analogs, nelfinavir was found to be superior to placebo, but abacavir was no better than older nucleoside analogs in pre-treated patients. Again, only about 30% of patients achieved undetectable plasma HIV RNA levels after sixteen weeks of treatment.

Overall, these studies suggested that new drugs are desperately needed if effective therapy is going to be available to pre-treated patients. In the meantime, physicians report that AIDS deaths in their heavily pre-treated patients are rising. Coalition members have targeted Abbott Laboratories' new protease inhibitor, known as ABT-378, as a likely candidate. In December, a group of more than one hundred activists wrote to Abbott demanding that the drug's utility as salvage therapy be rapidly tested, and that the company began plans for a pre-approval expanded access program. Representatives from Abbott have been meeting with the Coalition, and have reportedly promised that at the very least a limited program will be up and running by September, 1999.

Preliminary results of ABT-378 in patients who have experienced failure on one prior protease inhibitor were recently presented at a closed scientific meeting. While results from this study have not been distributed, insiders say that the drug looked as good in these pre-treated patients as it did in naive patients.

Coalition members also report that they have initiated conversations with Gilead Sciences about their experimental nucleotide inhibitor PMPA, with Trimeris, Inc. regarding its fusion inhibitor T-20, and with Pharmacia-Upjohn which is developing a new protease inhibitor known as Tipranavir.

In the meantime, providers are experimenting with "Mega-HAART" combinations that can include up to nine anti-HIV therapies at once. In a study conducted by Dr. Veronica Miller in Germany, thirty-seven heavily pre-treated patients were treated with six or more anti-HIV therapies. Patients were followed for a median period of eight months. Ten patients achieved undetectable plasma HIV RNA levels (<500 copies) throughout the follow-up period, while eight patients achieved but did not sustain the viral load reductions, while six patients never achieved undetectable viral load levels. Three patients discontinued treatment due to intolerance. Patients who had a "washout period" of more than two months were more likely to experience shifts in resistance patterns towards wild-type virus, and were also more likely to experience sustained reductions in plasma HIV RNA levels.

GENOTYPIC TESTS IMPROVE EFFICACY OF SECOND-LINE TREATMENT

Results from a study known as the Genotypic Antiretroviral Resistance Testing (GART) Study, conducte by the Community Program for Clinical Research on AIDS (CPCRA), have suggeste that using genotypic resistance testing following failure of a protease inhibitor-containing regimen can improve treatment results of the next treatment regimen.

Patients included in the study had experienced a three-fold or greater rise in HIV-RNA levels for at least sixteen weeks while taking an antiretroviral therapy regimen including two nucleoside analogs an a protease inhibitor. Participants also had CD4+ counts of 50-500 cells, and at least twelve months of prior antiretroviral therapy. When a patient was enrolled, his or her physician selected a regimen based solely on treatment history. Then half of patients had plasma samples assesse dfor genotypic evidence of resistance, and an expert panel recommended a treatment regimen based on the resistance test. Then the new treatment regimen was started.

After four to eight weeks of treatment, patients given resistance testing had about a half-log lower viral load than patients not given the resistance testing. Furthermore, patients given resistance testing were more likely to have plasma viral load counts below the limit of detection than patients not given resistance testing.

Genotypic resistance tests are currently available, but as no test has been approved by the FDA, many insurers do not pay for the tests. Upcoming additions to the Public Health Service Treatment Guidelines are expected to incorporate recommendations for resistance testing. An observational study of resistance testing in 30,000 patients, to be known as the VIGILANCE study, is currently enrolling patients.

VIAGRA AND PROTEASE INHIBITORS: INTERACTION RISKS

Erectile Dysfunction spokesman Bo Dole may not have anything to worry about, but according to Pfizer Pharmaceuticals, makers of the block buster impotence treatment Viagra, people taking protease inhibitors shoul be careful when using the drug. Studies have suggested that the anti-HIV medications can substantially increase levels of Viagra, which could, in turn, cause low blood pressure and increase the risk of heart attack.

In studies, saquinavir (marketed as Invirase or Fortovase) had a relatively mild effect on Viagra levels. Pfizer recommends that patients combining saquinavir an Viagra begin with 25mg of Viagra an increase dosing as necessary.

By contrast, ritonavir (marketed as Norvir) had a much more substantial effect on Viagra levels. Pfizer recommends that patients combining the two drugs should take no more than 25mg of Viagra within a forty-eight hour period.

In addition, a number of warnings have been distribute about the dangers of mixing Viagra with nitrate drugs. Inhaled nitrates, known as "poppers," are commonly use among gay men to enhance sexual pleasure.

SHOULD ANAL PAP SMEARS BE ROUTINE FOR HIV+ MEN?

New data from researchers at the Harvard School of Public Health suggests that anal pap smears may be a cost-effective way to reduce risk of anal cancer in HIV-positive men. Anal cancer rates are elevated for gay men as a group, and substantially elevated for HIV-positive gay men. The rate of anal cancer in the general population has een estimate at approximately 0.8 per 100,000, while the rate among gay men is estimate at 35 cases per 100,000, and about twice that for HIV-positive gay men.